Animals and humans suffer from endoparasitical infections including, for example, helminthiasis which is most frequently caused by a group of parasitic worms described as nematodes or roundworms. These parasites cause severe economic losses in pigs, sheep, horses, and cattle as well as poultry. Other parasites which occur in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius and parasites which are found in the blood or other tissues and organs such as filarial worms and the extra intestinal stages of Strongyloides, Toxocara and Trichinella. 
Because of bioavailability, efficacy, or dosing convenience concerns, many beneficial agents are preferably administered parenterally. Since a recipient could receive several dosage forms over a lifetime, it is essential that the dosage form leave little or no undesirable residue. Bioerodible polymeric dosage forms are ideally suited for these applications, and provide the additional advantage that drug delivery from a single dosage form may effectively treat the disease state for a prolonged period.
Known bioerodible polymeric controlled release devices can be generally categorized as either encapsulated devices or matrix devices. In encapsulated devices, beneficial agent (e.g., drug) is surrounded by a polymer layer which controls release of the beneficial agent. The beneficial agent in a matrix device, however, is dissolved or suspended in the polymer matrix and diffuses through the matrix, or is released in conjunction with the dissolution, disintegration, decomposition, or erosion of the matrix.
With matrix devices, beneficial agents can be incorporated into the matrix by physical entrapment or are chemically bound to the matrix. When exposed to a biological environment of use, the polymer matrix dissolves, disintegrates, decomposes, or erodes (i.e., degrades) to release beneficial agent. Significant experimental effort is required to “tune” the polymer/beneficial agent formulation to enable it to be stable and to release at the desired rate.
As regards treatment and prevention of parasitic infestation, a particularly important class of beneficial agents is the macrocyclic lactone, which may be used for treating endo- and ectoparasite infections in mammals and birds. Compounds that belong to this class include the avermectins and milbemycins. These compounds are potent antiparasitic agents against a wide range of internal and external parasites. Avermectins and milbemycins share the same common 16-membered macrocyclic lactone ring; however, milbemycins do not possess the disaccharide substituent on the 13-position of the lactone ring. In addition to treating parasitic insects, avermectins and milbemycins are used to treat endoparasites, e.g., round worm infections, in warm-blooded animals.
The avermectins may be isolated from the fermentation broth of an avermectin producing strain of Streptomyces avermitilis and derivatives thereof. The production, isolation and structural determination of the avermectins are documented in Albers-Schonberg, et. al, J. Am. Chem. Soc. 1981, 103, 4216-4221 and references cited therein. The description of the morphological characteristics of the culture is described in U.S. Pat. No. 4,310,519, which is incorporated herein by reference.
The milbemycins are the aglycone derivatives of the avermectins, such as those described, for example in U.S. Pat. Nos. 4,144,352; 4,791,134; and 6,653,342. A particularly important anthelmintic of this family includes moxidectin, as described, for example in U.S. Pat. No. 7,348,417; U.S. Pat. No. 4,900,753; U.S. Pat. No. 4,988,824; U.S. Pat. No. 5,106,994; U.S. Pat. No. 7,645,863; and U.S. Pat. No. 4,916,154 (and references cited therein). For milbemycins, reference may be made, inter alia, to Vercruysse, J. and Rew, R. S., editors, Macrocyclic Lactones in Antiparasitic Therapy, CABI International 2002; Campbell, William C., editor, Ivermectin and Abamectin, Springer-Verlag, 1989; Davies H. G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Pat. No. 4,134,973 and EP 0 677 054. As evidenced by the numerous references, amorphous moxidectin is well-known in the art, but other solid forms, including crystalline polymorphs and solvates/hydrates (pseudopolymorphs), have not been described.
U.S. Pat. No. 6,162,820 (to Merial) disclosed long-acting combinations of fipronil and ivermectin (an avermectin).
U.S. Pat. No. 6,733,767 (to Merck) disclosed a liquid polymeric composition for controlled release of eprinomectin, consisting essentially of the active ingredient, PLGA, and solvent mixture. The composition forms a depot upon injection into the animal.
U.S. Pat. No. 6,797,701 (to Pfizer) disclosed avermectin 13-monosaccharide 5-oxime formulations consisting essentially of the active ingredient and glycol ether.
U.S. Pat. No. 7,326,428 (to Rutgers University) disclosed (in its background section) ivermectin encapsulated in PLGA (50:50) microspheres. The subsequent pulsed release of this agent, in vivo, was shown to be dependent on the degradation rate of the polymer matrix.
US 2004/0241204 (to Martinod et al.) disclosed sustained release mini-implants or pellets in combination may provide a blood level of ivermectin active preferably 1 to 4 weeks. A list of potential polymers was disclosed, including PLGA, polyamino acids, PGS and Biopol.
Ivermectin was also successfully combined with PLGA to produce a biodegradable drug delivery matrix for use in dogs (Clark et al., AJVR 2004).
ProHeart 6 (Pfizer sustained-release moxidectin product) provided moxidectin sterile microspheres, however, the product was recalled on Sep. 3, 2004 due to adverse events, including death, thus illustrating the significant challenge in producing formulations capable of safely delivering beneficial agents, particularly moxidectin, over long periods of time.
In view of above references, there are several examples of macrocyclic lactone “microsphere” formulations, as well as “liquid polymer depot-type” formulations, but inventors are unaware of any polymeric moxidectin solid implant dosage forms as of the filing of this disclosure.
All of these documents and references cited therein, as well as the references cited herein, are expressly incorporated by reference.
Notwithstanding the excellent progress in antiparasitic research, concerns remain with respect to increasingly common reports of resistance among veterinary parasites (Parasitology 2005, 131, S179-190). Other concerns related to potential adverse effects on dung-dwelling insects essential for dung degradation have been raised with respect to endectocides. Thus, there remains an ongoing need for novel endectocides and anthelmintic treatments in veterinary medicine. It is an object of this invention to provide novel endectocides and anthelmintic compounds and formulations, as well as methods of treatment using such compounds. That the invention performs as herein described is surprising, unexpected and nonobvious.
All documents cited or referenced herein (“herein cited documents”), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention.
Citation or identification of any document in this application does not constitute an admission that such document is available as prior art to the present invention.